Cooling agents, pharmaceutical compositions having cooling agents and processes for making and using same

ABSTRACT

The invention pertains to cooling agents comprising N-substituted p-menthane-3-carboxamides, menthyl acetate and solubilizer, and methods for making the cooling agents. The invention also concerns pharmaceutical compositions comprising the cooling agents, including tablets, suspensions and liquid solutions having active pharmaceutical agents for treating upper gastrointestinal tract distress, and methods for treating upper gastrointestinal tract distress in humans.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to cooling agent compositions that impart acooling sensation to the skin and mucous membranes of the body,particularly the mouth, nose, throat and gastrointestinal tract duringconsumption and methods for making cooling agents. The cooling agentscomprise N-substituted p-menthane-3-carboxamides, menthyl acetate and asolubilizer, in spray dried form. The invention also concernspharmaceutical compositions comprising the cooling agents, includingtablets, suspensions and liquid solutions having active ingredients fortreating upper gastrointestinal tract distress, and methods for treatingupper gastrointestinal tract distress in humans. The cooling agents mayalso be used in a sundry of edible products such as confectionaryproducts, including chewing gum, hard and soft candies and the like.

[0003] 2. The Prior Art

[0004] Cooling agents and compositions are used in a sundry of consumergoods. U.S. Pat. No. 4,136,163 describes the use of N-substitutedp-menthane-3-carboxamides in edible and potable compositions,toiletries, medicaments, and miscellaneous compositions such asenvelopes, postage stamps and adhesive compositions. The N-substitutedp-menthane-3-carboxamides are described as having a physiologicalcooling effect on the skin and on the mucous membranes of the body,particularly the mouth, nose, throat and gastrointestinal tract. U.S.Pat. No. 4,060,091 describes the use of N-substitutedp-menthane-3-carboxamides in tobacco or tabacco containing products.

[0005] In pharmaceutical compositions, such as antacids, useful fortreating upper gastrointestinal tract distress, such as heartburn,indigestion, stomachache and the like, cooling agents are generallyemployed as excipients to provide cooling sensation when thepharmaceutic composition is consumed. Generally, the activepharmaceutical agent in pharmaceutical compositions for treating uppergastrointestinal tract distress will not immediately begin to relievethe condition causing the distress. Cooling agents, used in thepharmaceutical compositions as excipients, however, provide coolingsensation to the mouth, throat and gastrointestinal tract so that thepharmaceutical composition will be perceived by the consumer as actingfaster to alleviate the gastrointestinal distress. Thus, the consumer isprovided with the sensation of relief although the active principle ofthe pharmaceutical composition has not begun to alleviate the conditionscausing the distress.

[0006] U.S. Pat. No. 5,244,670 describes ingestible pharmaceuticalcompositions for treating upper gastrointestinal tract distresscomprising active principle and 3,1-methoxy propane 1,2-diol (“MPD”).U.S. Pat. No. 5,009,893 describes chewing gum compositions comprising acooling agent having from about 5% to about 70%, by weight, of mentholand from about 30% to about 95%, by weight, of N-substitutedp-menthane-3-carboxamide compounds. The combination of the menthol andthe carboxamide compounds in the amounts specified in U.S. Pat. No.5,009,893 are said to be necessary for cooling and breath fresheningproperties. U.S. Pat. No. 5,698,181 describes breath-freshening ediblecompositions comprising a cooling composition of essential ingredientsof about 94% to about 99.999%, by weight, menthol and about 0.001% toabout 6%, by weight, N-substituted p-menthane-3-carboxamides.

[0007] There is a consumer demand, and consequently a need, for coolingagents that provide faster cooling sensation when consumed and longerlasting effect. The art of cooling agents for pharmaceuticalcompositions, confectionary products and like comestibles is constantlyevolving.

[0008] It was an object of the invention to develop new cooling agentsfor use in comestible goods, like pharmaceutical compositions, andconfectionary products, like gum, that provide cooling effect and longlasting freshness.

[0009] We have discovered that cooling agents comprising the combinationof N-substituted p-menthane-3-carboxamides, menthyl acetate andsolubilizer, in spray dried form, act synergistically to provide coolingsensation and a long lasting freshness effect. The cooling agents areparticularly useful in pharmaceutical compositions for treating uppergastrointestinal tract distress.

[0010] In the present Specification, all parts and percentages are byweight/weight unless otherwise specified. The term “by weight of coolingagent components” as used herein means the weight percentage based onthe total weight of all of the components of the cooling agent, such asthe carboxamide, menthyl acetate and solubilizer. The term “by weight ofthe combination” as used herein means the weight percentage based on thetotal weight of all of the components of the cooling agent and thecarrier and residual water in the spray dried particles. The term “byweight of the pharmaceutical composition” as used herein means theweight percentage based on the total weight of all components of thepharmaceutical composition.

SUMMARY OF THE INVENTION

[0011] The invention pertains to cooling agents comprising N-substitutedp-menthane-3-carboxamides, menthyl acetate and a solubilizer. Thefinished cooling agent is in spray dried form and, in that state, can beused in a number of products, including pharmaceutical compositions,particularly those for treating upper gastrointestinal tract distress,and confectionary products. The menthyl acetate is combined with theN-substituted p-menthane-3-carboxamides and the combination actssynergistically to provide the cooling effect and long lasting freshnessthat characterizes the invention.

[0012] The N-substituted p-menthane-3-carboxamides, menthyl acetate andsolubilizer can be made through spray drying processes. For example, thecooling agent can be combined with a carrier and water to form anemulsion for spray drying to obtain spray dried particulate materialcomprising the cooling agent and a carrier. The solubilizer in thecooling agent prevents the N-substituted p-menthane-3-carboxamides fromcrystallizing out of solution during the spray drying process, whichrequires heat to maintain solubility.

DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1 is a graph showing average sensory perception for coolingat time intervals after ingestion of pharmaceutical compositionscomprising the cooling agents.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The cooling agents comprise about 1% to about 20%, preferablyabout 10% to about 20%, N-substituted p-menthane-3-carboxamides, byweight of cooling agent components, about 1% to about 10%, preferablyabout 3% to about 6%, menthyl acetate, by weight of cooling agentcomponents, and about 60% to about 85%, preferably about 75% to about85%, solubilizer, by weight of cooling agent components. The coolingagents may also consist essentially of the foregoing components or mayconsist of the foregoing components. It was unexpectedly discovered thatthe combination of these compounds within these compositional ranges,particularly the N-substituted p-menthane-3-carboxamides and menthylacetate, act synergistically to provide cooling sensation and longlasting freshness. The solubilizer stabilizes the solution so that theN-substituted p-menthane-3-carboxamides will not crystallize out duringthe spray drying process as a result of the heat that must be appliedduring the process.

[0015] The N-substituted p-menthane-3-carboxamides used in the inventiongenerally have the following formula:

[0016] where

[0017] 1) R′, when taken separately, is hydrogen or an aliphatic radicalcontaining up to 25 carbon atoms;

[0018] 2) R″, when taken separately is hydroxy, or an aliphatic radicalcontaining up to 25 carbon atoms, with the proviso that when R′ ishydrogen R″ may also be an aryl radical of up to 10 carbon atoms andselected from the group consisting of substituted phenyl, phenalkyl orsubstituted phenalkyl, naphthyl and substituted naphthyl, pyridyl; and

[0019] 3) R′ and R″, when taken together with the nitrogen atom to whichthey are attached, represent a cyclic or heterocyclic group of up to 25carbon atoms, e.g. piperidino, morpholino and the like.

[0020] In the above definitions “aliphatic” is intended to include anystraight-chained, branched-chained or cyclic free radical or aromaticunsaturation, and thus embraces alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, hydroxyalkyl, acyloxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, acylaminoalkyl, carboxyalkyl and similar combinations.

[0021] Typical values for R′ and R″ when aliphatic are methyl, ethyl,propyl, butyl, isobutyl, n-decyl, cyclopropyl, cyclohexyl, cyclopentyl,cycloheptylmethyl, 2-hydroxyethyl, 3-hydroxy-n-propyl,6-hydroxy-n-hexyl, 2-aminoethyl, 2-acetoxyethyl, 2-ethylcarboxyethyl,4-hydroxybut-2-ynyl, carboxymethyl and the like.

[0022] When R″ is aryl typical values are benzyl, naphthyl,4-methoxyphenyl, 4-hydroxyphenyl, 4-methylphenyl,3-hydroxy-4-methylphenyl, 4-fluorophenyl, 4-nitrophenyl,2-hydroxynaphthyl, pyridyl, and the like.

[0023] The preferred species is N-ethyl p-menthane-3-carboxamide, whichis commercially known as “WS-3”. N-ethyl p-menthane-3-carboxamide isavailable from Millennium Specialty Chemicals, Jacksonville, Fla., USA.

[0024] The N-substituted p-menthane-3-carboxamides may be readilyprepared by conventional methods, such as by the reaction of thecorresponding acid chloride (obtained by reactingp-menthane-3-carboxylic acid with thionyl chloride) with the appropriatemono- or di-substituted amine. The reaction will usually be carried outin solution in the presence of a hydrogen chloride receptor, e.g. sodiumhydroxide. The reaction proceeds smoothly at room temperature.

[0025] The carboxamide compounds exhibit both geometric and opticalisomerism and, depending on the starting materials and the methods usedin their preparation, the compounds may be isometrically pure, i.e.consisting of one geometric or optical isomer, or they may be isomericmixtures, both in the geometric and optical sense. The basic p-menthanestructure is a chair-shaped molecule which can exist in cis or transforms. Substitution of the carboxyl or amide group into the 3-positiongives rise to four configurational or geometric isomers depending uponwhether the substitution is axially or equatorially into the cis ortrans isomer, the four isomers being related as menthol is toneomenthol, isomenthol, and neoisomenthol. In general it is found thatin the compounds used in this invention the equatorially substitutedderivatives have the greater cooling effect than the axial compounds andare to be preferred. Substitution of the amide group in the 3-positionof the p-menthane structure also gives rise to optical isomerism, eachof the above-mentioned four geometric isomers, existing in d, I and dIforms.

[0026] When either R′ and R″ is aliphatic, the preferred values areC₁-C₉ straight or branched chain alkyl, C₁-C₉ straight or branched chainhydroxyalkyl or aminoalkyl and C₁-C₄ acrylated derivatives thereof, and—C_(n)H_(2n)COR′″ or —C_(n)H_(2n)COOR′″, where —C_(n)H_(2n) is astraight or branched chain alkylene radical in which n is an integer offrom 1-6 and R′″ is hydrogen or a C₁-C₈ alkyl or hydroxyalkyl group,preferably a C₁-C₄ straight chain alkyl group.

[0027] In general the monosubstituted compounds, i.e. where R′ is H, arepreferred although di-substituted compounds where R′ and R″ are bothC₁-C₃ alkyl may be used. Most preferred of all are compounds where R′ isH and R″ is C₁-C₃ alkyl, C₁-C₄ hydroxyalkyl, or —CH₂COOR′″, where R′″ isC₁-C₄ alkyl.

[0028] Also included are compounds where R′ is H and R″ is hydroxy orsubstituted phenyl, e.g. alkylphenyl, hydroxyphenyl, alkoxyphenyl,halophenyl of up to 10 carbon atoms, phenalkyl or substituted phenalkyl,e.g. benzyl, naphthyl or substituted naphthyl, and compounds where R′and R″ are joined to form a cyclic group. When so joined R′ and R″preferably represent an alkylene chain, optionally interrupted byoxygen, which together with the nitrogen atom to which R′ and R″ areattached forms a 5- or 6-membered heterocyclic ring.

[0029] Menthyl acetate is a colorless liquid having a chemical formulaof C₁₂H₂₂O₂. Menthyl acetate is a constituent of peppermint oil and canbe derived from the natural oil, or obtained by chemical synthesisthrough processes that would be known to one skilled in the art. Menthylacetate is available from Haarmann & Reimer, South Plainfield, N.J.,USA.

[0030] The solubilizer provides stability to the N-substitutedp-menthane-3-carboxamide during the spray drying process by preventingthe carboxamide from crystallizing out as a result of the heat that isapplied during the spray drying process. Suitable solubilizers aremiglyol which are mixed esters of capric and acrylic acids that areesterified on glycerin, ethoxylated hydrogenated castor oil,polysorbates, glycerin, triglycerides and fatty acids such as lauricacid, myristic acid, palmitic acid, stearic acid, oleic acid, linolenicacid and the like. The preferred solubilizer is miglyol, such as thatavailable from LIPO Chemicals, Inc., Paterson, N.J., USA under thetradename LIPONATE™ (GC-K).

[0031] The cooling agent can be incorporated into a spray driedparticulate material through a spray drying process. The N-substitutedp-menthane-3-carboxamide, menthyl acetate and solubilizer are generallycombined with a suitable carrier, such as Salseal 200 available fromNational Starch, Bridgewater, N.J., USA or starches as would be known toone skilled in the art, and water to form an emulsion. The emulsion isspray dried in either a conical or flat bottom spray drier, depending onproduction volume, at speed rates, temperature, pressure and nozzle sizeto obtain spray dried particulate material comprising the cooling agenthaving a particle size permitting 100% of the particles to pass througha 40 mesh screen. The ratio of cooling agent, e.g. N-substitutedp-menthane-3-carboxamide, menthyl acetate and solubilizer, to carrier inthe particulates is about 50:50 to about 90:10, preferably about 70:30,by weight of the combination.

[0032] The cooling agents and the particulates comprising the coolingagent may be incorporated in a number of consumer products, includingpharmaceutical compositions and confectionary products. When used inpharmaceutical compositions, particularly those for treating uppergastrointestinal tract distress, such as heartburn, indigestion,stomachache and the like, the cooling agents, or the particulatecomprising the cooling agents, are excipients which may be combined withactive pharmaceutical agents and other excipients and then be compressedinto tablets or used in liquid form, such as solutions, suspensions oremulsions and the like.

[0033] Active pharmaceutical agents for treating upper gastrointestinaltract distress are those materials which are safe and effective whenadministered orally for treating disorders of the upper gastrointestinaltract (typically the stomach and/or esophagus) which result in symptomsof upper gastrointestinal tract distress. Such active pharmaceuticalagents include antacid agents and acid secretion prevention agents(e.g., H₂ receptor-blocking antisecretory agents). Antacid agentsinclude, for example, aluminum carbonate, aluminum hydroxide, aluminumphosphate, aluminum hydroxy-carbonate, dihydroxy aluminum sodiumcarbonate, aluminum magnesium glycinate, dihydroxy aluminum aminoacetate, dihydroxy aluminum aminoacetic acid, calcium carbonate, calciumphosphate, aluminum magnesium hydrated sulfates, magnesium aluminate,magnesium alumina silicates, magnesium carbonate, magnesium glycinate,magnesium hydroxide, magnesium oxide, magnesium trisilicate, sucralfate,and mixtures thereof. Examples of acid secretion prevention agentsinclude cimetidine, ranitidine, famotidine, omeprazole, and mixturesthereof. Other useful pharmaceutical actives include bismuth-containingagents such as, for example, bismuth subsalicylate, bismuth aluminate,bismuth citrate, bismuth subcitrate, bismuth nitrate, bismuthsubcarbonate, bismuth subgalate, and mixtures thereof. A particularlypreferred bismuth salt is bismuth subsalicylate.

[0034] Preferred antacid agents are aluminum hydroxide, magnesiumhydroxide, dihydroxy aluminum sodium carbonate, calcium carbonate, andmixtures thereof. Most preferred is calcium carbonate.

[0035] The pharmaceutical compositions comprise a safe and effectiveamount of at least one active pharmaceutical agent, useful for treatingupper gastrointestinal tract distress. Typically the activepharmaceutical agent(s) are from about 1% to about 99%, preferably fromabout 30% to about 40%, by weight of the pharmaceutical composition.

[0036] The pharmaceutical compositions also comprise the cooling agentsdescribed herein which comprise N-substituted p-menthane-3-carboxamide,menthyl acetate and solubilizer. The cooling agent and, optionallyresidual water and/or carrier when the cooling agent is used in theparticulate form, are generally present in the pharmaceuticalcompositions in an amount of about 0.01% to about 1%, preferably about0.05% to about 0.25%, by weight of the pharmaceutical composition.

[0037] In addition, excipients other than the cooling agent mayoptionally be included in the pharmaceutical compositions. The term“excipient(s)”, as used herein, means, in addition to the cooling agent,one or more compatible solid or liquid filler diluents or encapsulatingsubstances which are suitable for oral administration to a human andencompasses all of the ingredients of the pharmaceutical compositionsexcept the active pharmaceutical agent. The term “compatible”, as usedherein, means that the components of the compositions of the inventionare capable of being commingled with the active pharmaceutical agent,and with each other, in a manner such that there is no interaction whichwould substantially reduce the pharmaceutical efficacy of thecompositions under ordinary use situations. Excipients must, of course,be of sufficiently high purity and sufficiently low toxicity to renderthem suitable for administration to the human being.

[0038] Some examples of substances which can serve as excipients aresugars such as lactose, glucose and sucrose; starches such as cornstarchand potato starch; cellulose and its derivatives such as sodiumcarboxymethylcellulose, ethylcellulose, cellulose acetate; powderedtragacanth; malt; gelatin; talc; stearic acid; magnesium stearate;calcium sulfate; vegetable oils such as peanut oil, cottonseed oil,sesame oil, olive oil, corn oil and oil of theobroma; polyols such aspropylene glycol, glycerine, sorbitol, mannitol, and polyethyleneglycol; agar; and alginic acid; as well as other non-toxic compatiblesubstances used in pharmaceutical formulations. Wetting agents andlubricants such as sodium lauryl sulfate, as well as coloring agents,flavoring agents, sweetening agents (including normutritive sweetenerssuch as aspartame and saccharine), tableting agents, stabilizers,antioxidants, and preservatives, can also be present. Other compatiblepharmaceutical additives and actives which are not active pharmaceuticalagents useful for treating upper gastrointestinal tract distress (e.g.,NSAI drugs; pain killers; muscle relaxants) may be included in thecompositions of the present invention. Also, it is to be noted that inaddition to the cooling agents described herein, other materials havingcooling properties may optionally be included within the excipients,such as menthol cooling compounds and mixtures thereof. Menthol or othermaterials having cooling properties, however, are not necessary to theunexpected and surprising cooling performance (i.e. the coolingsensation and long lasting freshness perceived by the consumer) of thecooling agents comprising N-substituted p-menthane-3-carboxamides,menthyl acetate and solubilizer.

[0039] The choice of excipients to be used in conjunction with theactive pharmaceutical agent is basically determined by the dose form forthe pharmaceutical compositions. The preferred dosage forms are tablets,especially chewable tablets, capsules and the like, comprising a safeand effective amount of the active pharmaceutical agent(s). Dosage formsmay also include liquid solutions, liquid suspensions and the like.Excipients suitable for the preparation of dosage forms for oraladministration are well-known in the art. Their selection will depend onsecondary considerations like taste, cost, shelf stability, and can bemade without difficulty by a person skilled in the art.

[0040] The excipients employed in the ingestible compositions are usedat concentrations sufficient to provide a practical size to dosagerelationship. Typically, excipients comprise from about 1% to about 99%,preferably from about 85% to about 99%, by weight of the pharmaceuticalcomposition.

[0041] The pharmaceutical compositions comprising the cooling agent orthe particulate described herein, comprising N-substitutedp-menthane-3-carboxamide compounds, menthyl acetate and solubilizer,preferably miglyol, can be employed in methods for treating uppergastrointestinal tract distress in humans. The method comprises orallyadministering to a human a safe and effective amount of at least oneactive pharmaceutical agent useful for treating upper gastrointestinaltract distress and an amount of the cooling agent effective to provide acooling sensation to the mouth, throat and for the gastrointestinaltract. The preferred mode of administration for this method is throughan ingestible composition, most preferably through an ingestible tablet.

EXAMPLE

[0042] Cooling agent comprising 15% N-ethyl p-menthane-3-carboxamide, 5%menthyl acetate and 80% miglyol 810 from LIPO Chemicals, Inc., all byweight of cooling agent components, with a carrier in particulate formwas incorporated into tablet form pharmaceutical compositions comprisingcalcium carbonate, an active pharmaceutical agent of an antacid agent,and orange fruit flavorings. Tablets containing cooling agent withcarrier, the particulate, at 0.1% by weight of the pharmaceuticalcomposition and at 0.2% by weight of the pharmaceutical composition wereprepared.

[0043] The tablets were then provided to a tasting panel for sensoryTotal Oral Perception using a sliding ballot scale of 0 for no coolingeffect to 6 for high cooling effect. Each panelist sampled one and twotablets of each pharmaceutical composition comprising cooling agent inparticulate form with carrier at 0.1% and 0.2% by weight of thepharmaceutical composition.

[0044] The testing study was performed for 3 days with two tastingsessions daily. The testing protocol for one tablet required eachpanelist to place one tablet in the mouth, chew twenty times andswallow. Cooling perception measurements were recorded privately by eachpanelist at 30 seconds after swallowing the sample tablet and thereafterat 30 second intervals for a total time of six minutes. The testingprotocol for two tablets required the panelist to place one fruit tabletin the mouth, chew twenty times, swallow, place the second tablet in themouth, chew 20 times and swallow. Cooling perception measurements wererecorded privately by each panelist at 30 seconds after swallowing thesecond tablet contents and thereafter at 30 second intervals for a totaltime of six minutes.

[0045] The ballots were reviewed to obtain average perception scoresbased on a sliding scale of 0-6 for the three day trials for one tabletand two tablets having the cooling agent with carrier, in particulateform at, respectively, 0.1% and 0.2% by weight of the pharmaceuticalcomposition. The results are presented in FIG. 1.

1. A cooling agent comprising: a) N-substituted p-menthane-3-carboxamideof the formula:

where R′, when taken separately, is hydrogen or an aliphatic radicalcontaining up to 25 carbon atoms; and R″, when taken separately ishydroxy, or an aliphatic radical containing up to 25 carbon atoms, withthe proviso that when R′ is hydrogen R″ may also be an aryl radical ofup to 10 carbon atoms and selected from the group consisting ofsubstituted phenyl, phenalkyl, substituted phenalkyl, naphthyl,substituted naphthyl, and pyridyl; and R′ and R″, when taken togetherwith the nitrogen atom to which they are attached, represent a cyclic orheterocyclic group of up to 25 carbon atoms, b) menthyl acetate, and c)solubilizer.
 2. The cooling agent of claim 1 comprising from about 1% toabout 20% of the N-substituted p-menthane-3-carboxamide, about 1% toabout 10% of the menthyl acetate and about 60% to about 85% of thesolubilizer all by weight of cooling agent components.
 3. The coolingagent of claim 1 wherein the N-substituted p-menthane-3-carboxamidecompound is N-ethyl p-methane-3-carboxamide.
 4. The cooling agent ofclaim 1 in combination with a carrier.
 5. The cooling agent of claim 1wherein the solubilizer is selected from the group consisting ofmiglyol, ethoxylated hydrogenated castor oil, polysorbates, glycerin,triglycerides and fatty acids.
 6. The cooling agent of claim 5 whereinthe fatty acids are selected from the group consisting of lauric acid,myristic acid, palmitic acid, stearic acid, oleic acid and linolenicacid.
 7. A pharmaceutical composition comprising from about 1% to about99% by weight of the pharmaceutical composition of at least one activepharmaceutical agent selected from the group consisting of antacidagents, acid secretion prevention agents, bismuth containing agents andmixtures thereof and from about 1% to about 99% by weight of thepharmaceutical composition excipients comprising at least one coolingagent, wherein the cooling agent comprises a) N-substitutedp-menthane-3-carboxamide of the formula:

where R′, when taken separately, is hydrogen or an aliphatic radicalcontaining up to 25 carbon atoms; and R″, when taken separately ishydroxy, or an aliphatic radical containing up to 25 carbon atoms, withthe proviso that when R′ is hydrogen R″ may also be an aryl radical ofup to 10 carbon atoms and selected from the group consisting ofsubstituted phenyl, phenalkyl, substituted phenalkyl, naphthyl,substituted naphthyl, and pyridyl; and R′ and R″, when taken togetherwith the nitrogen atom to which they are attached, represent a cyclic orheterocyclic group of up to 25 carbon atoms, b) menthyl acetate, and c)solubilizer.
 8. The pharmaceutical composition of claim 7 wherein thecooling agent comprises from about 1% to about 20% of the N-substitutedp-menthane-3-carboxamide compounds, about 1% to about 10% of the menthylacetate and about 60% to about 85% of the solubilizer all by weight ofcooling agent components
 9. The pharmaceutical composition of claim 7further comprising a carrier.
 10. The pharmaceutical composition ofclaim 7 wherein the N-substituted p-menthane-3-carboxamide is N-ethylp-methane-3-carboxamide.
 11. The pharmaceutical composition of claim 7wherein the excipients comprise menthol.
 12. The pharmaceuticalcomposition of claim 7 wherein the antacid agents are selected from thegroup consisting of aluminum carbonate, aluminum-hydroxide, aluminumphosphate, aluminum hydroxy-carbonate, dihydroxy aluminum sodiumcarbonate, aluminum magnesium glycinate, dihydroxy aluminum aminoacetate, dihydroxy aluminum aminoacetic acid, calcium carbonate, calciumphosphate, aluminum magnesium hydrated sulfates, magnesium aluminate,magnesium alumina silicates, magnesium carbonate, magnesium glycinate,magnesium hydroxide, magnesium oxide, magnesium trisilicate, sucralfate,and mixtures thereof.
 13. The pharmaceutical composition of claim 7wherein the acid secretion prevention agents are selected from the groupconsisting of cimetidine, ranitidine, famotidine, omeprazole, andmixtures thereof.
 14. The pharmaceutical composition of claim 7 whereinthe bismuth containing agents are selected from the group consisting ofbismuth subsalicylate, bismuth aluminate, bismuth citrate, bismuthsubcitrate, bismuth nitrate, bismuth subcarbonate, bismuth subgalate,and mixtures thereof.
 15. A method for treating upper gastrointestinaltract distress in humans comprising orally administering through aningestible composition a safe and effective amount of at least oneactive pharmaceutical agent and the cooling agent of claim
 1. 16. Themethod of claim 15 wherein the ingestible composition is in the form oftablet.
 17. A method for making spray-dried particulate materialcomprising a cooling agent and a carrier comprising the steps ofcombining N-substituted p-menthane-3-carboxamide, menthyl acetate andsolubilizer with a carrier and water to form an emulsion then spraydrying the emulsion wherein the N-substituted p-menthane-3-carboxamideis of the formula:

where R′, when taken separately, is hydrogen or an aliphatic radicalcontaining up to 25 carbon atoms; and R″, when taken separately ishydroxy, or an aliphatic radical containing up to 25 carbon atoms, withthe proviso that when R′ is hydrogen R″ may also be an aryl radical ofup to 10 carbon atoms and selected from the group consisting ofsubstituted phenyl, phenalkyl, substituted phenalkyl, naphthyl,substituted naphthyl, and pyridyl; and R′ and R″, when taken togetherwith the nitrogen atom to which they are attached, represent a cyclic orheterocyclic group of up to 25 carbon atoms.
 18. The method of claim 17wherein the N-substituted p-menthane-3-carboxamide is N-ethylp-methane-3-carboxamide.
 19. The method of claim 17 wherein thesolubilizer is selected from the group consisting of miglyol,ethoxylated hydrogenated castor oil, polysorbates, glycerin,triglycerides and fatty acids.
 20. The method of claim 19 wherein thefatty acids are selected from the group consisting of lauric acid,myristic acid, palmitic acid, stearic acid, oleic acid and linolenicacid.